Psychiatric Aspects of HIV
by Mary Romeyn, MD
In this article, adapted from a February 1997 Grand Rounds presentation
at Saint Francis Memorial Hospital in San Francisco, a San Francisco physician
with a large AIDS practice speaks to medical professionals about dealing
with the unique psychiatric needs of HIV positive men and women.
As with any process that imposes high levels of stress on the body over
a long period of time, the spectrum of consequences of HIV infection frequently
includes psychiatric manifestations. Recognizing and treating these conditions
is only a beginning. The patient and doctor also must consider the potential
for drug interactions between psychiatric medications and drugs used to
manage HIV disease, and must adjust dosages as needed.
This article will attempt to:
1) summarize some of the latest developments in the study of psychiatric
manifestations of HIV disease;
2) review those manifestations associated with drugs commonly used to
manage HIV disease;
3) draw attention to the potential for drug interactions; and
4) address treatment issues relevant to the psychiatric care of people
with HIV.
Depression
Depression has been reported in 4-14% of people living with HIV. One
long-term study evaluating men with HIV disease at 6-month intervals for
8 years reported that over 50% met the criteria for clinical depression
at least once during that time. With intensifying depression, the risk
of death was found to increase by two-thirds, independent of CD4 cell
counts. Thus it makes sense to diagnose depression early, eliminate external
causes, and treat this condition.
In the medical literature, depression has been associated with many medications
commonly used by people with HIV disease, including AZT (Retrovir), acyclovir
(Zovirax), sulfonamide antibiotics, anticonvulsants, narcotics and isoniazid
(INH). However, in clinical practice, a clear association between these
medications and depression is relatively infrequent. If a drug suspected
of causing depression is not critical to the maintenance of health or
suppression of viral load and -- if the patient and doctor both agree
-- a brief trial discontinuation of the drug may be tried to see if symptoms
resolve.
Depression may occur during withdrawal from androgenic steroids. A slow
taper schedule may be appropriate if withdrawal from an anabolic steroid
is thought to be a factor in depression.
N. Sacktor, MD and colleagues, from Johns Hopkins University School of
Medicine, reported on a study of 31 HIV-infected men, 19 of whom were
classified with HIV encephalopathy (brain disease). They reported 2 distinct
symptom-complex subtypes. Common to both groups were a tendency toward
depressed mood, frequent crying and confusion. While physical symptoms
and a feeling of being overwhelmed were more common in the group with
encephalopathy, the group with a CD4 cell count of greater than 200 cells/mm3
and no evidence of encephalopathy showed more classic symptoms of depression,
less self-esteem and more social withdrawal than the group with encephalopathy.
The researchers suggest that the difference in patterns of depression
between these 2 subtypes may argue for a trial of different medication
strategies in each group. A physician experienced with different strategies
might explore various treatment options.
The use of recreational drugs must also be considered when depression
exists. Effects of multiple substance abuse and/or withdrawal can be difficult
to tease out when superimposed on a regimen of multiple therapeutic drugs
and their interactions. Treatment decisions must reflect the likelihood
and nature of recreational drug use and the potential for additive toxicities.
Treatment must also take into account the potential for drug interactions.
The protease inhibitor ritonavir (Norvir), for instance -- by inhibiting
the cytochrome P450 enzymes in the liver that process and excrete a wide
variety of medications -- can increase tricyclic antidepressant (TCA)
drug levels by 1.5-3 times, and increase levels of fluoxetine (Prozac)
and paroxetine (Paxil), both selective serotonin reuptake inhibitor (SSRI)
antidepressants, by 19% and 150%, respectively. Levels of sertraline (Zoloft)
-- another SSRI -- may be increased by more than 300% in the presence
of ritonavir, and probably should not be used in this setting. Because
of its long half-life, fluoxetine also should be avoided with ritonavir,
because high drug levels in the blood that can cause neurologic or cardiac
effects decrease slowly.
When SSRI drugs are used in combination with TCA drugs, blood levels
of SSRI drugs can rise even higher. Low doses and close observation of
people on such regimens are appropriate.
SSRI at therapeutic doses can reduce sexual desire and delay ejaculation.
At toxic levels, one may see serotonin syndrome -- tremor, agitation,
hypomania (a mild degree of mania), tachycardia (rapid heart beat), vomiting,
headache and even psychosis (thought disorder). TCA drugs at toxic levels
can alter heart function. Sedation and confusion may also be seen. At
therapeutic levels, dry mouth and drowsiness are significant side effects.
When appropriate doses are used, drowsiness diminishes with regular use.
Other antidepressants include bupropion (Wellbutrin), which is contraindicated
in patients with a history of seizures and in those taking ritonavir;
nefazodone (Serzone), with drug levels increased by more than 3 times
in the presence of ritonavir; and trazodone (Desyrel) and venlafaxine
(Effexor), with levels of each drug increased by 1.5-3 times when taken
with ritonavir.
Anxiety
Anxiety is common, especially at the time of HIV diagnosis or disease
progression. Anxiety has been associated with the use of several medications,
including corticosteroids, nonsteroidal anti-inflammatory drugs and sulfonamide
antibiotics. Treatment is complicated by concerns about drug interactions
with protease inhibitors and other drugs that use the CP450 system. Since
blood levels of all benzodiazepine tranquilizers except lorazepam (Ativan),
oxazepam (Serax) and temazepam (Restoril) are greatly increased in the
presence of ritonavir, their use is contraindicated. Lorazepam, oxazepam
and temazepam are metabolized more quickly in the presence of ritonavir,
and may require increased dosage to achieve the intended effect. Because
midazolam (Versed) and triazolam (Halcion) are metabolized more slowly
when given with indinavir (Crixivan), dosages may need to be reduced.
Mania
Mania may be difficult to treat. The condition has been associated with
the use of AZT, dapsone, androgenic steroids and corticosteroids, and
may be exacerbated by the use of antidepressants. Disinhibition (leading
to inappropriate behavior) and increased stressors may unmask an existing
tendency toward mania. Where possible, the best approach is to treat the
underlying cause.
The use of lithium requires very careful monitoring. Many drugs used
to treat HIV and related conditions may impair kidney functioning and
may cause lithium to concentrate in the kidneys. In addition, diarrhea
and dehydration are common in HIV disease; lithium toxicity is increased
in dehydrated patients. Perphenazine (Trilafon), valproic acid (Depakote)
and carbamazepine (Tegretol) have been used successfully in people with
HIV. Carbamazepine must be used judiciously because it may worsen bone
marrow suppression caused by other HIV drugs. In addition, carbamazepine
is itself a potent CP450 inducer. It can reduce blood levels of pro-tease
inhibitors, thus predisposing the patient to the development of drug resistance.
Delirium
Delirium (confusion) has an underlying cause. The condition may result
from changes in drug levels due to drug interactions. It can also be seen
with corticosteroid (e.g., prednisone), opiate (e.g., codeine) or TCA
drug use. While delirium has been associated in clinical studies with
acyclovir and the class of antibiotics called quinolones, this is rarely
seen clinical practice.
Medical causes such as electrolyte imbalance, abnormal blood sugar levels,
or reduced oxygen or increased carbon dioxide in the blood often underlie
delirium. Where possible, one should treat the problem by treating its
cause. If antipsychotic drugs are needed, high potency neuroleptics such
as haloperidol (Haldol) should be used only briefly, as their side effects
are reportedly more common in people with HIV.
Psychosis
Psychosis is characterized by the presence of auditory and visual hallucinations,
delusions or other related disorders. When psychosis is present, it is
important to look for all possible causes. Drug interactions (such as
those noted elsewhere in this article) and the possibility of new central
nervous system disease (e.g., a tumor) should be considered.
Because an increased tendency for neuroleptic malignant syndrome (a life-threatening
condition characterized by confusion, high blood pressure, fever and involuntary
muscle movements) and other motor abnormalities have been reported with
high potency neuroleptics, these drugs must be used judiciously. Chlorpromazine
(Thorazine), perphenazine (Trilafon), thioridazine (Mellaril), haloperidol
and risperidone (Risperdal) are all increased 1.5-3 times in the presence
of ritonavir. Clozapine (Clozaril) and pimozide (Orap) are contraindicated
with ritonavir.
Dementia
Manifestations of dementia, or HIV encephalopathy (also known as AIDS
dementia complex or HIV-associated dementia) usually appear late in the
course of HIV disease and have not always been found to be related to
levels of viral load in the cerebrospinal fluid. Infection of the central
nervous system is necessary, but not sufficient, to cause encephalopathy.
Immune activation, the body's response to infection, is also required.
(See AIDS Dementia Complex, BETA, December
1996.)
Macrophage activation plays an important causal role in dementia. When
activated, macrophages pump out a variety of factors which damage neurons
and impair their function. These factors include proinflammatory cytokines,
platelet activating factor, nitric oxide and free radicals. Immune system
activity directed against the invading virus damages cells in the brain.
In addition, macrophage activation results in the release of more viral
particles, initiating new cycles of infection.
Dementia is treatable. Optimal treatment requires early recognition while
the symptoms are still reversible, vigorous treatment with high-dose antiretrovirals
that cross the blood-brain barrier and consideration of neuroprotective
agents and agents that block immune activation.
AZT is the nucleoside analog drug with the best central nervous system
penetration. The dual combinations of AZT plus 3TC and d4T plus 3TC have
been shown to decrease HIV RNA levels in cerebrospinal fluid to undetectable
levels. Nonnucleoside reverse transcriptase inhibitors (NNRTI) are also
powerful drugs. Nevirapine (Viramune) crosses the blood-brain barrier
rapidly, in high concentration. Delavirdine (Rescriptor) concentrates
in brain tissue at a level 4-5 times higher than that found in plasma.
When using these NNRTI, it is important to consider their effects on protease
inhibitor concentrations. Nevirapine appears to lower blood levels of
protease inhibitors, while delavirdine appears to increase them. However,
no change in dosage is necessary when either nevirapine or delavirdine
is combined with either ritonavir or saquinavir. Selegiline (Deprenyl
or Eldepryl), a monoamine oxidase inhibitor used to treat Parkinson's
disease, has been reported to have efficacy for HIV-associated dementia.
Conclusion
Use of psychiatric medications in people with HIV disease is complex
and demanding. Issues of potential drug interactions and the need for
careful planning and coordination of therapeutic efforts make providing
psychiatric care and stabilization difficult.
Mary Romeyn, MD, is Medical Director of the Andrew Ziegler Foundation.
She is author of Nutrition and HIV: A New Model for Treatment and is a
member of the San Francisco AIDS Foundation's Scientific Advisory Committee.
The author gratefully acknowledges the assistance and review of Evelyn
Rose, PhD, clinical pharmacologist at Saint Francis Memorial Hospital
in San Francisco.
References
Power C and others. HIVdementia scale: a rapid screening
test. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology
8:273-278. 1995.
Sacktor N and others. Depression subtypes in HIV infection.
Fourth Conference on Retroviruses and Opportunistic Infections. January
1997. Abstract 348.
Capaldini L. Psychiatric complications and psychosocial
issues in HIV disease. AIDSfile 8:2. June 1994.
Bowers M. AIDS dementia complex. BETA:11-15.
December 1996.
Page last updated 1 April 1997
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